Oligomer-cannabinoid conjugates

ABSTRACT

The invention relates to (among other things) oligomer-cannabinoid conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over previously administered un-conjugated cannabinoid compounds.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.12/865,372, filed 6 Oct. 2011, which is a 35 U.S.C. §371 application ofInternational Application No. PCT/US2009/000810, filed 6 Feb. 2009,designating the United States, which claims the benefit of priorityunder 35 U.S.C. §119(e) to U.S. Provisional Patent Application Ser. No.61/065,089, filed 8 Feb. 2008, all of which are incorporated herein byreference in their entireties.

FIELD OF THE INVENTION

This invention comprises (among other things) chemically modifiedcannabinoids that possess certain advantages over cannabinoids lackingthe chemical modification. The chemically modified cannabinoidsdescribed herein relate to and/or have application(s) in (among others)the fields of drug discovery, pharmacotherapy, physiology, organicchemistry and polymer chemistry.

BACKGROUND OF THE INVENTION Neuropathic Pain

Two cannabinoid receptors have been identified. CB₁, present in thecentral nervous system (CNS) and to a lesser extent in other tissues,and CB₂, present outside the CNS, in peripheral organs. There isevidence for the presence of CB₂-like receptors in peripheral nerveterminals. In recent years there has been indirect evidence for themodulation of pain through CB₂ receptor mechanisms. As a result, therehas been an effort to develop and evaluate CB₂-selective agonists suchas HU308, AM1241, JWH-133, and GW405833. These compounds have providedsupport for the hypothesis that activation of CB₂ producesantinociceptive effects in persistent pain states. Other compounds,CP55,940 and WIN55,212-2 are agonists that have high affinity for bothCB₁ and CB₂ receptors and which also have been shown to suppress pain inanimals. As with most cannabinoids, there is substantial evidence thatthese compounds cross the blood brain barrier (BBB). As a result, thereare CNS side effects which may limit their use. The need exists fortherapies and management of chronic to severe pain without the unwantedside effects.

Obesity

The cannabinoid rimonabant is approved in the European Union (asACOMPLIA™) as an adjunct to diet and exercise for the treatment of obesepatients that also have associated risk factors, such as type 2 diabetesor dyslipidaemia. Rimonabant is a selective cannabinoid CB₁ receptorantagonist (or inverse agonist), with little or no affinity for otherreceptors. This interaction with peripheral CB₁ receptors has been shownto reduce food intake and body weight when given acutely. There issubstantial evidence that Rimonabant crosses the BBB. As a result, thereare significant side effects which may limit its use.

Inflammation

The cannabinoid Dronabinol is currently used for chemotherapy-inducednausea and vomiting refractory to conventional antiemetics. Cannabinoidsare being investigated for a number of other conditions including thetreatment of inflammatory conditions like psoriasis. For this use, it isconsidered a Type 3 drug (centrally acting drug with potentiallytherapeutic peripheral activity).

Pharmacologically, cannabinoid drugs represent an important class ofagents employed in the management of pain, obesity, inflammation, andalso in combating drug addiction, alcohol addiction, smoking cessation,drug overdose, mental illness, urinary incontinence, cough, lung edema,diarrhea, depression, and cognitive, respiratory, and gastro-intestinaldisorders, immunomodulation, migraine, asthma, epilepsy, glaucoma,Parkinson's disease, dyskinesia, neuropathy, memory and thymicdisorders, vomiting, ischemia, angor, orthostatic hypotension, cardiacinsufficiency, stress, anxio-depressive disorders orpsychosomatic-induced disorders. However, administration of cannabinoiddrugs results in significant side effects. Thus, a reduction of theseside effects would enhance their desirability as therapeutic agents. Asa consequence, there is a large unmet need for developing novelcannabinoid compounds.

The present invention seeks to address these and other needs in the art.

SUMMARY OF THE INVENTION

In one or more embodiments of the invention, a compound is provided, thecompound comprising a cannabinoid residue covalently attached via astable or degradable linkage to a water-soluble, non-peptidic oligomer.

In other embodiments of the invention, a compound is provided, thecompound comprising a cannabinoid residue covalently attached via astable or degradable linkage to a water-soluble, non-peptidic oligomer,wherein the cannabinoid residue is other than tetrahydrocannabinol, alsoknown as dronabinol.

Exemplary compounds of the invention include those having the followingstructure:

wherein:g₂, g₃, g₄, g₅, and g₆ and w₂, w₃, w₄, w₅ and w₆ are identical ordifferent and are independently hydrogen, a chlorine atom or a bromineatom, a (C₁-C₃)-alkyl, a (C₁-C₃)-alkoxy, a trifluoromethyl or a nitrogroup and g₄ is optionally a phenyl group;R₄ is hydrogen or a (C₁-C₃)-alkyl;A is either a direct bond or a group —(CH₂)_(x)—N(R₃)—, in which R₃ ishydrogen or a (C₁-C₃)-alkyl and x is zero or one; and,R₁ is a (C₁-C₆)-alkyl; an optionally-substituted non-aromatic (C₃-C₁₅)carbocyclic radical; an amino (C₁-C₄) alkyl group in which the amino isoptionally disubstituted by a (C₁-C₃)-alkyl; a cycloalkyl-(C₁-C₃) alkylin which the cycloalkyl is C₃-C₁₂; a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, by a (C₁-C₅)-alkyl orby a (C₁-C₅)-alkoxy; a phenyl (C₁-C₃)-alkyl; a diphenyl-(C₁-C₃)-alkyl; anaphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclicradical which is unsubstituted or substituted by a (C₁-C₃)-alkyl, by ahydroxyl or by a benzyl group; a 1-adamantylmethyl; an aromaticheterocycle unsubstituted, mono- or polysubstituted by a halogen, a(C₁-C₅)-alkyl, a (C₁-C₅)-alkoxy; a (C₁-C₃)-alkyl substituted by anaromatic heterocycle unsubstituted or mono- or polysubstituted by ahalogen, a (C₁-C₅) alkyl, or a (C₁-C₅)-alkoxy;X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

wherein:g₂, g₃, g₅, and g₆ and w₂, w₃, w₄, w₅ and w₆ are identical or differentand are independently hydrogen, a chlorine atom or a bromine atom, a(C₁-C₃)-alkyl, a (C₁-C₃)-alkoxy, a trifluoromethyl or a nitro group andg₄ is optionally a phenyl group;R₄ is hydrogen or a (C₁-C₃)-alkyl;A is either a direct bond or a group —(CH₂)_(x)—N(R₃)—, in which R₃ ishydrogen or a (C₁-C₃)-alkyl and x is zero or one; and,R₁ is a (C₁-C₆)-alkyl; an optionally-substituted non-aromatic (C₃-C₁₅)carbocyclic radical; an amino (C₁-C₄) alkyl group in which the amino isoptionally disubstituted by a (C₁-C₃)-alkyl; a cycloalkyl-(C₁-C₃) alkylin which the cycloalkyl is C₃-C₁₂; a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, by a (C₁-C₅)-alkyl orby a (C₁-C₅)-alkoxy; a phenyl (C₁-C₃)-alkyl; a diphenyl-(C₁-C₃)-alkyl; anaphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclicradical which is unsubstituted or substituted by a (C₁-C₃)-alkyl, by ahydroxyl or by a benzyl group; a 1-adamantylmethyl; an aromaticheterocycle unsubstituted, mono- or polysubstituted by a halogen, a(C₁-C₅)-alkyl, a (C₁-C₅)-alkoxy; a (C₁-C₃)-alkyl substituted by anaromatic heterocycle unsubstituted or mono- or polysubstituted by ahalogen, a (C₁-C₅) alkyl, or a (C₁-C₅)-alkoxy;X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

wherein:g₂, g₃, g₄, g₅, and g₆ and w₃, w₄, w₅ and w₆ are identical or differentand are independently hydrogen, a chlorine atom or a bromine atom, a(C₁-C₃)-alkyl, a (C₁-C₃)-alkoxy, a trifluoromethyl or a nitro group andg₄ is optionally a phenyl group;R₄ is hydrogen or a (C₁-C₃)-alkyl;A is either a direct bond or a group —(CH₂)_(x)—N(R₃)—, in which R₃ ishydrogen or a (C₁-C₃)-alkyl and x is zero or one; and,R₁ is a (C₁-C₆)-alkyl; an optionally-substituted non-aromatic (C₃-C₁₅)carbocyclic radical; an amino (C₁-C₄) alkyl group in which the amino isoptionally disubstituted by a (C₁-C₃)-alkyl; a cycloalkyl-(C₁-C₃) alkylin which the cycloalkyl is C₃-C₁₂; a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, by a (C₁-C₅)-alkyl orby a (C₁-C₅)-alkoxy; a phenyl (C₁-C₃)-alkyl; a diphenyl-(C₁-C₃)-alkyl; anaphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclicradical which is unsubstituted or substituted by a (C₁-C₃)-alkyl, by ahydroxyl or by a benzyl group; a 1-adamantylmethyl; an aromaticheterocycle unsubstituted, mono- or polysubstituted by a halogen, a(C₁-C₅)-alkyl, a (C₁-C₅)-alkoxy; a (C₁-C₃)-alkyl substituted by anaromatic heterocycle unsubstituted or mono- or polysubstituted by ahalogen, a (C₁-C₅) alkyl, or a (C₁-C₅)-alkoxy;X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

wherein:g₂, g₃, g₄, g₅, and g₆ and w₂, w₃, w₅ and w₆ are identical or differentand are independently hydrogen, a chlorine atom or a bromine atom, a(C₁-C₃)-alkyl, a (C₁-C₃)-alkoxy, a trifluoromethyl or a nitro group andg₄ is optionally a phenyl group;R₄ is hydrogen or a (C₁-C₃)-alkyl;A is either a direct bond or a group —(CH₂)_(x)—N(R₃)—, in which R₃ ishydrogen or a (C₁-C₃)-alkyl and x is zero or one; and,R₁ is a (C₁-C₆)-alkyl; an optionally-substituted non-aromatic (C₃-C₁₅)carbocyclic radical; an amino (C₁-C₄) alkyl group in which the amino isoptionally disubstituted by a (C₁-C₃)-alkyl; a cycloalkyl-(C₁-C₃) alkylin which the cycloalkyl is C₃-C₁₂; a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, by a (C₁-C₅)-alkyl orby a (C₁-C₅)-alkoxy; a phenyl (C₁-C₃)-alkyl; a diphenyl-(C₁-C₃)-alkyl; anaphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclicradical which is unsubstituted or substituted by a (C₁-C₃)-alkyl, by ahydroxyl or by a benzyl group; a 1-adamantylmethyl; an aromaticheterocycle unsubstituted, mono- or polysubstituted by a halogen, a(C₁-C₅)-alkyl, a (C₁-C₅)-alkoxy; a (C₁-C₃)-alkyl substituted by anaromatic heterocycle unsubstituted or mono- or polysubstituted by ahalogen, a (C₁-C₅) alkyl, or a (C₁-C₅)-alkoxy;X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention may utilize one or morepositions of the defined structures of formulae I an II to attach thelinker X to the water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

The “cannabinoid residue” is a compound having a structure of acannabinoid compound that is altered by the presence of one or morebonds, which bonds serve to attach (either directly or indirectly) oneor more water-soluble, non-peptidic oligomers.

In this regard, any cannabinoid compound having cannabinoid receptorbinding activity can be used as a cannabinoid moiety. Exemplarycannabinoid moieties have a structure encompassed by Formula I:

wherein:g₂, g₃, g₄, g₅, and g₆ and w₂, w₃, w₄, w₅ and w₆ are identical ordifferent and are independently hydrogen, a chlorine atom or a bromineatom, a (C₁-C₃)-alkyl, a (C₁-C₃)-alkoxy, a trifluoromethyl or a nitrogroup and g₄ is optionally a phenyl group;R₄ is hydrogen or a (C₁-C₃)-alkyl;A is either a direct bond or a group —(CH₂)_(x)—N(R₃)—, in which R₃ ishydrogen or a (C₁-C₃)-alkyl and x is zero or one; and,R₁ is (C₁-C₆)-alkyl; an optionally-substituted non-aromatic (C₃-C₁₅)carbocyclic radical; an amino (C₁-C₄) alkyl group in which the amino isoptionally disubstituted by a (C₁-C₃)-alkyl; a cycloalkyl-(C₁-C₃) alkylin which the cycloalkyl is C₃-C₁₂; a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, by a (C₁-C₅)-alkyl orby a (C₁-C₅)-alkoxy; a phenyl (C₁-C₃)-alkyl; a diphenyl-(C₁-C₃)-alkyl; anaphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclicradical which is unsubstituted or substituted by a (C₁-C₃)-alkyl, by ahydroxyl or by a benzyl group; a 1-adamantylmethyl; an aromaticheterocycle unsubstituted, mono- or polysubstituted by a halogen, a(C₁-C₅)-alkyl, a (C₁-C₅)-alkoxy; a (C₁-C₃)-alkyl substituted by anaromatic heterocycle unsubstituted or mono- or polysubstituted by ahalogen, a (C₁-C₅) alkyl, or a (C₁-C₅)-alkoxy.

In one or more embodiments of the invention, a composition is provided,the composition comprising a compound comprising a cannabinoid residuecovalently attached via a stable or degradable linkage to awater-soluble, non-peptidic oligomer, and optionally, a pharmaceuticallyacceptable excipient.

In one or more embodiments of the invention, a dosage form is provided,the dosage form comprising a compound comprising a cannabinoid residuecovalently attached via a stable or degradable linkage to awater-soluble, non-peptidic oligomer, wherein the compound is present ina dosage form.

In one or more embodiments of the invention, a method is provided, themethod comprising covalently attaching a water-soluble, non-peptidicoligomer to a cannabinoid moiety.

In one or more embodiments of the invention, a method is provided, themethod comprising administering a compound comprising a cannabinoidresidue covalently attached via a stable or degradable linkage to awater-soluble, non-peptidic oligomer.

These and other objects, aspects, embodiments and features of theinvention will become more fully apparent to one of ordinary skill inthe art when read in conjunction with the following detaileddescription.

DETAILED DESCRIPTION OF THE INVENTION

As used in this specification, the singular forms “a,” “an,” and “the”include plural referents unless the context clearly dictates otherwise.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions describedbelow.

“Water soluble, non-peptidic oligomer” indicates an oligomer that is atleast 35% (by weight) soluble, preferably greater than 70% (by weight),and more preferably greater than 95% (by weight) soluble, in water atroom temperature. Typically, an unfiltered aqueous preparation of a“water-soluble” oligomer transmits at least 75%, more preferably atleast 95%, of the amount of light transmitted by the same solution afterfiltering. It is most preferred, however, that the water-solubleoligomer is at least 95% (by weight) soluble in water or completelysoluble in water. With respect to being “non-peptidic,” an oligomer isnon-peptidic when it has less than 35% (by weight) of amino acidresidues.

The terms “monomer,” “monomeric subunit” and “monomeric unit” are usedinterchangeably herein and refer to one of the basic structural units ofa polymer or oligomer. In the case of a homo-oligomer, a singlerepeating structural unit forms the oligomer. In the case of aco-oligomer, two or more structural units are repeated—either in apattern or randomly—to form the oligomer. Preferred oligomers used inconnection with present the invention are homo-oligomers. Thewater-soluble, non-peptidic oligomer typically comprises one or moremonomers serially attached to form a chain of monomers. The oligomer canbe formed from a single monomer type (i.e., is homo-oligomeric) or twoor three monomer types (i.e., is co-oligomeric).

An “oligomer” is a molecule possessing from about 1 to about 30monomers. Specific oligomers for use in the invention include thosehaving a variety of geometries such as linear, branched, or forked, tobe described in greater detail below.

“PEG” or “polyethylene glycol,” as used herein, is meant to encompassany water-soluble poly(ethylene oxide). Unless otherwise indicated, a“PEG oligomer” or an oligoethylene glycol is one in which substantiallyall (preferably all) monomeric subunits are ethylene oxide subunits,though, the oligomer may contain distinct end capping moieties orfunctional groups, e.g., for conjugation. PEG oligomers for use in thepresent invention will comprise one of the two following structures:“—(CH₂CH₂O)_(n)-” or “—(CH₂CH₂O)_(n-1)CH₂CH₂—,” depending upon whetheror not the terminal oxygen(s) has been displaced, e.g., during asynthetic transformation. As stated above, for the PEG oligomers, thevariable (n) ranges from about 1 to 30, and the terminal groups andarchitecture of the overall PEG can vary. When PEG further comprises afunctional group, A, for linking to, e.g., a small molecule drug, thefunctional group when covalently attached to a PEG oligomer does notresult in formation of (i) an oxygen-oxygen bond (—O—O—, a peroxidelinkage), or (ii) a nitrogen-oxygen bond (N—O, O—N).

The terms “end-capped” or “terminally capped” are interchangeably usedherein to refer to a terminal or endpoint of a polymer having anend-capping moiety. Typically, although not necessarily, the end-cappingmoiety comprises a hydroxy or C₁₋₂₀ alkoxy group. Thus, examples ofend-capping moieties include alkoxy (e.g., methoxy, ethoxy andbenzyloxy), as well as aryl, heteroaryl, cyclo, heterocyclo, and thelike. In addition, saturated, unsaturated, substituted and unsubstitutedforms of each of the foregoing are envisioned. Moreover, the end-cappinggroup can also be a silane. The end-capping group can alsoadvantageously comprise a detectable label. When the polymer has anend-capping group comprising a detectable label, the amount or locationof the polymer and/or the moiety (e.g., active agent) of interest towhich the polymer is coupled, can be determined by using a suitabledetector. Such labels include, without limitation, fluorescers,chemiluminescers, moieties used in enzyme labeling, colorimetricmoieties (e.g., dyes), metal ions, radioactive moieties, and the like.Suitable detectors include photometers, films, spectrometers, and thelike. In addition, the end-capping group may contain a targeting moiety.

The term “targeting moiety” is used herein to refer to a molecularstructure that helps the conjugates of the invention to localize to atargeting area, e.g., help enter a cell, or bind a receptor. Preferably,the targeting moiety comprises of vitamin, antibody, antigen, receptor,DNA, RNA, sialyl Lewis X antigen, hyaluronic acid, sugars, cell specificlectins, steroid or steroid derivative, RGD peptide, ligand for a cellsurface receptor, serum component, or combinatorial molecule directedagainst various intra- or extracellular receptors. The targeting moietymay also comprise a lipid or a phospholipid. Exemplary phospholipidsinclude, without limitation, phosphatidylcholines, phospatidylserine,phospatidylinositol, phospatidylglycerol, and phospatidylethanolamine.These lipids may be in the form of micelles or liposomes and the like.The targeting moiety may further comprise a detectable label oralternately a detectable label may serve as a targeting moiety. When theconjugate has a targeting group comprising a detectable label, theamount and/or distribution/location of the polymer and/or the moiety(e.g., active agent) to which the polymer is coupled can be determinedby using a suitable detector. Such labels include, without limitation,fluorescers, chemiluminescers, moieties used in enzyme labeling,colorimetric (e.g., dyes), metal ions, radioactive moieties, goldparticles, quantum dots, and the like.

“Branched,” in reference to the geometry or overall structure of anoligomer, refers to an oligomer having two or more polymers “arms”extending from a branch point.

“Forked,” in reference to the geometry or overall structure of anoligomer, refers to an oligomer having two or more functional groups(typically through one or more atoms) extending from a branch point.

A “branch point” refers to a bifurcation point comprising one or moreatoms at which an oligomer branches or forks from a linear structureinto one or more additional arms.

The term “reactive” or “activated” refers to a functional group thatreacts readily or at a practical rate under conventional conditions oforganic synthesis. This is in contrast to those groups that either donot react or require strong catalysts or impractical reaction conditionsin order to react (i.e., a “nonreactive” or “inert” group).

“Not readily reactive,” with reference to a functional group present ona molecule in a reaction mixture, indicates that the group remainslargely intact under conditions that are effective to produce a desiredreaction in the reaction mixture.

A “protecting group” is a moiety that prevents or blocks reaction of aparticular chemically reactive functional group in a molecule undercertain reaction conditions. The protecting group may vary dependingupon the type of chemically reactive group being protected as well asthe reaction conditions to be employed and the presence of additionalreactive or protecting groups in the molecule. Functional groups whichmay be protected include, by way of example, carboxylic acid groups,amino groups, hydroxyl groups, thiol groups, carbonyl groups and thelike. Representative protecting groups for carboxylic acids includeesters (such as ap-methoxybenzyl ester), amides and hydrazides; foramino groups, carbamates (such as tert-butoxycarbonyl) and amides; forhydroxyl groups, ethers and esters; for thiol groups, thioethers andthioesters; for carbonyl groups, acetals and ketals; and the like. Suchprotecting groups are well-known to those skilled in the art and aredescribed, for example, in T. W. Greene and G. M. Wuts, ProtectingGroups in Organic Synthesis, Third Edition, Wiley, New York, 1999, andreferences cited therein.

A functional group in “protected form” refers to a functional groupbearing a protecting group. As used herein, the term “functional group”or any synonym thereof encompasses protected forms thereof.

A “physiologically cleavable” or “hydrolyzable” or “degradable” bond isa relatively labile bond that reacts with water (i.e., is hydrolyzed)under physiological conditions. The tendency of a bond to hydrolyze inwater may depend not only on the general type of linkage connecting twocentral atoms but also on the substituents attached to these centralatoms. Appropriate hydrolytically unstable or weak linkages include butare not limited to carboxylate ester, phosphate ester, anhydrides,acetals, ketals, acyloxyalkyl ether, imines, orthoesters, peptides,oligonucleotides, thioesters, and carbonates.

An “enzymatically degradable linkage” means a linkage that is subject todegradation by one or more enzymes.

A “stable” linkage or bond refers to a chemical bond that issubstantially stable in water, that is to say, does not undergohydrolysis under physiological conditions to any appreciable extent overan extended period of time. Examples of hydrolytically stable linkagesinclude but are not limited to the following: carbon-carbon bonds (e.g.,in aliphatic chains), ethers, amides, urethanes, amines, and the like.Generally, a stable linkage is one that exhibits a rate of hydrolysis ofless than about 1-2% per day under physiological conditions. Hydrolysisrates of representative chemical bonds can be found in most standardchemistry textbooks.

“Substantially” or “essentially” means nearly totally or completely, forinstance, 95% or greater, more preferably 97% or greater, still morepreferably 98% or greater, even more preferably 99% or greater, yetstill more preferably 99.9% or greater, with 99.99% or greater beingmost preferred of some given quantity.

“Monodisperse” refers to an oligomer composition wherein substantiallyall of the oligomers in the composition have a well-defined, singlemolecular weight and defined number of monomers, as determined bychromatography or mass spectrometry. Monodisperse oligomer compositionsare in one sense pure, that is, substantially having a single anddefinable number (as a whole number) of monomers rather than a largedistribution. A monodisperse oligomer composition possesses a MW/Mnvalue of 1.0005 or less, and more preferably, a MW/Mn value of 1.0000.By extension, a composition comprised of monodisperse conjugates meansthat substantially all oligomers of all conjugates in the compositionhave a single and definable number (as a whole number) of monomersrather than a large distribution and would possess a MW/Mn value of1.0005, and more preferably, a MW/Mn value of 1.0000 if the oligomerwere not attached to the therapeutic moiety. A composition comprised ofmonodisperse conjugates may, however, include one or more nonconjugatesubstances such as solvents, reagents, excipients, and so forth.

“Bimodal,” in reference to an oligomer composition, refers to anoligomer composition wherein substantially all oligomers in thecomposition have one of two definable and different numbers (as wholenumbers) of monomers rather than a large distribution, and whosedistribution of molecular weights, when plotted as a number fractionversus molecular weight, appears as two separate identifiable peaks.Preferably, for a bimodal oligomer composition as described herein, eachpeak is generally symmetric about its mean, although the size of the twopeaks may differ. Ideally, the polydispersity index of each peak in thebimodal distribution, Mw/Mn, is 1.01 or less, more preferably 1.001 orless, and even more preferably 1.0005 or less, and most preferably aMW/Mn value of 1.0000. By extension, a composition comprised of bimodalconjugates means that substantially all oligomers of all conjugates inthe composition have one of two definable and different numbers (aswhole numbers) of monomers rather than a large distribution and wouldpossess a MW/Mn value of 1.01 or less, more preferably 1.001 or less andeven more preferably 1.0005 or less, and most preferably a MW/Mn valueof 1.0000 if the oligomer were not attached to the therapeutic moiety. Acomposition comprised of bimodal conjugates may, however, include one ormore nonconjugate substances such as solvents, reagents, excipients, andso forth.

A “cannabinoid moiety” is broadly used herein to refer to an organic,inorganic, or organometallic compound typically having a molecularweight of less than about 1000 Daltons (and typically less than 500Daltons) and having some degree of activity as cannabinoid activity.Cannabinoid compounds of the invention encompass oligopeptides and otherbiomolecules having a molecular weight of less than about 1000 Daltons.

A “biological membrane” is any membrane made of cells or tissues thatserves as a barrier to at least some foreign entities or otherwiseundesirable materials. As used herein a “biological membrane” includesthose membranes that are associated with physiological protectivebarriers including, for example: the blood-brain barrier (BBB); theblood-cerebrospinal fluid barrier; the blood-placental barrier; theblood-milk barrier; the blood-testes barrier; and mucosal barriersincluding the vaginal mucosa, urethral mucosa, anal mucosa, buccalmucosa, sublingual mucosa, and rectal mucosa. Unless the context clearlydictates otherwise, the term “biological membrane” does not includethose membranes associated with the middle gastro-intestinal tract(e.g., stomach and small intestines).

A “biological membrane crossing rate,” provides a measure of acompound's ability to cross a biological membrane, such as theblood-brain barrier (“BBB”). A variety of methods may be used to assesstransport of a molecule across any given biological membrane. Methods toassess the biological membrane crossing rate associated with any givenbiological barrier (e.g., the blood-cerebrospinal fluid barrier, theblood-placental barrier, the blood-milk barrier, the intestinal barrier,and so forth), are known, described herein and/or in the relevantliterature, and/or may be determined by one of ordinary skill in theart.

A “reduced rate of metabolism” refers to a measurable reduction in therate of metabolism of a water-soluble oligomer-small molecule drugconjugate as compared to the rate of metabolism of the small moleculedrug not attached to the water-soluble oligomer (i.e., the smallmolecule drug itself) or a reference standard material. In the specialcase of “reduced first pass rate of metabolism,” the same “reduced rateof metabolism” is required except that the small molecule drug (orreference standard material) and the corresponding conjugate areadministered orally. Orally administered drugs are absorbed from thegastro-intestinal tract into the portal circulation and may pass throughthe liver prior to reaching the systemic circulation. Because the liveris the primary site of drug metabolism or biotransformation, asubstantial amount of drug may be metabolized before it ever reaches thesystemic circulation. The degree of first pass metabolism, and thus, anyreduction thereof, may be measured by a number of different approaches.For instance, animal blood samples may be collected at timed intervalsand the plasma or serum analyzed by liquid chromatography/massspectrometry for metabolite levels. Other techniques for measuring a“reduced rate of metabolism” associated with the first pass metabolismand other metabolic processes are known, described herein and/or in therelevant literature, and/or may be determined by one of ordinary skillin the art. Preferably, a conjugate of the invention may provide areduced rate of metabolism reduction satisfying at least one of thefollowing values: at least about 30%; at least about 40%; at least about50%; at least about 60%; at least about 70%; at least about 80%; and atleast about 90%. A compound (such as a small molecule drug or conjugatethereof) that is “orally bioavailable” is one that preferably possessesa bioavailability when administered orally of greater than 25%, andpreferably greater than 70%, where a compound's bioavailability is thefraction of administered drug that reaches the systemic circulation inunmetabolized form.

“Alkyl” refers to a hydrocarbon chain, ranging from about 1 to 20 atomsin length. Such hydrocarbon chains are preferably but not necessarilysaturated and may be branched or straight chain. Exemplary alkyl groupsinclude methyl, ethyl, propyl, butyl, pentyl, 2-methylbutyl,2-ethylpropyl, 3-methylpentyl, and the like. As used herein, “alkyl”includes cycloalkyl when three or more carbon atoms are referenced. An“alkenyl” group is an alkyl of 2 to 20 carbon atoms with at least onecarbon-carbon double bond.

The terms “substituted alkyl” or “substituted C_(q-r) alkyl” where q andr are integers identifying the range of carbon atoms contained in thealkyl group, denotes the above alkyl groups that are substituted by one,two or three halo (e.g., F, Cl, Br, I), trifluoromethyl, hydroxy, C₁₋₇alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, and soforth), C₁₋₇ alkoxy, C₁₋₇ acyloxy, C₃₋₇ heterocyclic, amino, phenoxy,nitro, carboxy, acyl, cyano. The substituted alkyl groups may besubstituted once, twice or three times with the same or with differentsubstituents.

“Lower alkyl” refers to an alkyl group containing from 1 to 6 carbonatoms, and may be straight chain or branched, as exemplified by methyl,ethyl, n-butyl, i-butyl, t-butyl. “Lower alkenyl” refers to a loweralkyl group of 2 to 6 carbon atoms having at least one carbon-carbondouble bond.

“Non-interfering substituents” are those groups that, when present in amolecule, are typically non-reactive with other functional groupscontained within the molecule.

“Alkoxy” refers to an —O—R group, wherein R is alkyl or substitutedalkyl, preferably C₁-C₂₀ alkyl (e.g., methoxy, ethoxy, propyloxy, etc.),preferably C₁-C₇.

“Pharmaceutically acceptable excipient” or “pharmaceutically acceptablecarrier” refers to component that may be included in the compositions ofthe invention causes no significant adverse toxicological effects to apatient.

The term “aryl” means an aromatic group having up to 14 carbon atoms.Aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl,naphthalenyl, and the like. “Substituted phenyl” and “substituted aryl”denote a phenyl group and aryl group, respectively, substituted withone, two, three, four or five (e.g. 1-2, 1-3 or 1-4 substituents) chosenfrom halo (F, Cl, Br, I), hydroxy, cyano, nitro, alkyl (e.g., C₁₋₆alkyl), alkoxy (e.g., C₁₋₆ alkoxy), benzyloxy, carboxy, aryl, and soforth.

Chemical moieties are defined and referred to throughout primarily asunivalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless,such terms are also used to convey corresponding multivalent moietiesunder the appropriate structural circumstances clear to those skilled inthe art. For example, while an “alkyl” moiety generally refers to amonovalent radical (e.g., CH₃—CH₂—), in certain circumstances a bivalentlinking moiety can be “alkyl,” in which case those skilled in the artwill understand the alkyl to be a divalent radical (e.g., —CH₂—CH₂—),which is equivalent to the term “alkylene.” (Similarly, in circumstancesin which a divalent moiety is required and is stated as being “aryl,”those skilled in the art will understand that the term “aryl” refers tothe corresponding multivalent moiety, arylene). All atoms are understoodto have their normal number of valences for bond formation (i.e., 1 forH, 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending onthe oxidation state of the S).

“Pharmacologically effective amount,” “physiologically effectiveamount,” and “therapeutically effective amount” are used interchangeablyherein to mean the amount of a water-soluble oligomer-small moleculedrug conjugate present in a composition that is needed to provide adesired level of active agent and/or conjugate in the bloodstream or inthe target tissue. The precise amount may depend upon numerous factors,e.g., the particular active agent, the components and physicalcharacteristics of the composition, intended patient population, patientconsiderations, and may readily be determined by one skilled in the art,based upon the information provided herein and available in the relevantliterature.

A “difunctional” oligomer is an oligomer having two functional groupscontained therein, typically at its termini. When the functional groupsare the same, the oligomer is said to be homodifunctional. When thefunctional groups are different, the oligomer is said to beheterodifunctional.

A basic reactant or an acidic reactant described herein include neutral,charged, and any corresponding salt forms thereof.

The term “patient,” refers to a living organism suffering from or proneto a condition that can be prevented or treated by administration of aconjugate as described herein, and includes both humans and animals.

“Optional” or “optionally” means that the subsequently describedcircumstance may but need not necessarily occur, so that the descriptionincludes instances where the circumstance occurs and instances where itdoes not.

“Nil” refers to the absence of a substituent group. Thus, when asubstituent is nil, the substituent may be represented in the structureas a chemical bond or hydrogen in the resulting structure.

As indicated above, the present invention is directed to (among otherthings) a compound comprising a cannabinoid residue covalently attachedvia a stable or degradable linkage to a water-soluble, non-peptidicoligomer.

The “cannabinoid residue” is a compound having a structure of acannabinoid compound that is altered by the presence of one or morebonds, which bonds serve to attach (either directly or indirectly) oneor more water-soluble, non-peptidic oligomers. Exemplary cannabinoidshave a structure encompassed by at least one of the structures definedherein as Formula I:

wherein:g₂, g₃, g₄, g₅, and g₆ and w₂, w₃, w₄, w₅ and w₆ are identical ordifferent and are independently hydrogen, a chlorine atom or a bromineatom, a (C₁-C₃)-alkyl, a (C₁-C₃)-alkoxy, a trifluoromethyl or a nitrogroup and g₄ is optionally a phenyl group;R₄ is hydrogen or a (C₁-C₃)-alkyl;A is either a direct bond or a group —(CH₂)_(x)—N(R₃)—, in which R₃ ishydrogen or a (C₁-C₃)-alkyl and x is zero or one; and,R₁ is a (C₁-C₆)-alkyl; an optionally-substituted non-aromatic (C₃-C₁₅)carbocyclic radical; an amino (C₁-C₄) alkyl group in which the amino isoptionally disubstituted by a (C₁-C₃)-alkyl; a cycloalkyl-(C₁-C₃) alkylin which the cycloalkyl is C₃-C₁₂; a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, by a (C₁-C₅)-alkyl orby a (C₁-C₅)-alkoxy; a phenyl (C₁-C₃)-alkyl; a diphenyl-(C₁-C₃)-alkyl; anaphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclicradical which is unsubstituted or substituted by a (C₁-C₃)-alkyl, by ahydroxyl or by a benzyl group; a 1-adamantylmethyl; an aromaticheterocycle unsubstituted, mono- or polysubstituted by a halogen, a(C₁-C₅)-alkyl, a (C₁-C₅)-alkoxy; a (C₁-C₃)-alkyl substituted by anaromatic heterocycle unsubstituted or mono- or polysubstituted by ahalogen, a (C₁-C₅) alkyl, a (C₁-C₅)-alkoxy.

In some instances, the “cannabinoid residue” is a compound having astructure of a cannabinoid compound that is altered by the presence ofone or more bonds, which bonds serve to attach (either directly orindirectly) one or more water-soluble, non-peptidic oligomers. Exemplarycannabinoids have a structure encompassed by at least one of thestructures defined herein as Formula Ig:

wherein:g₂, g₃, g₄, g₅, and g₆ and w₂, w₃, w₄, w₅ and w₆ are identical ordifferent and are independently hydrogen, a chlorine atom or a bromineatom, a (C₁-C₃)-alkyl, a (C₁-C₃)-alkoxy, a trifluoromethyl or a nitrogroup and g₄ is optionally a phenyl group;R₄ is hydrogen or a (C₁-C₃)-alkyl;A is either a direct bond or a group —(CH₂)_(x)—N(R₃)—, in which R₃ ishydrogen or a (C₁-C₃)-alkyl and x is zero or one; and,R is a group —NR₁R₂ in which R₁ and R₂ are independently a(C₁-C₆)-alkyl; an optionally-substituted non-aromatic (C₃-C₁₅)carbocyclic radical; an amino (C₁-C₄) alkyl group in which the amino isoptionally disubstituted by a (C₁-C₃)-alkyl; a cycloalkyl-(C₁-C₃) alkylin which the cycloalkyl is C₃-C₁₂; a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, by a (C₁-C₅)-alkyl orby a (C₁-C₅)-alkoxy; a phenyl (C₁-C₃)-alkyl; a diphenyl-(C₁-C₃)-alkyl; anaphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclicradical which is unsubstituted or substituted by a (C₁-C₃)-alkyl, by ahydroxyl or by a benzyl group; a 1-adamantylmethyl; an aromaticheterocycle unsubstituted, mono- or polysubstituted by a halogen, a(C₁-C₅)-alkyl, a (C₁-C₅)-alkoxy; a (C₁-C₃)-alkyl substituted by anaromatic heterocycle unsubstituted or mono- or polysubstituted by ahalogen, a (C₁-C₅) alkyl, a (C₁-C₅)-alkoxy, or else R₁ is hydrogen andR₂ is as defined above, or else R₁ and R₂, together with the nitrogenatom to which they are bonded, form a saturated 5- to 8-memberedheterocyclic radical, said heterocyclic radical being other thanmorpholine when g₂, g₃, g₄, g₅, and g₆ and w₂, w₃, w₄, w₅ and w₆ are allhydrogen;a group R₂ as defined above when A is —(CH₂)_(x)N(R₃)—; ora group R₅ when A is a direct bond, R₅ being a (C₁-C₃)-alkyl; a(C₃-C₁₂)-cycloalkyl which is unsubstituted or substituted by a(C₁-C₅)-alkyl; a phenyl-(C₁-C₃)-alkyl which is unsubstituted orsubstituted by a halogen or by a (C₁-C₅)-alkyl; acycloalkyl-(C₁-C₃)-alkyl in which the cycloalkyl is C₃-C₁₂ and isunsubstituted or substituted by a (C₁-C₅)-alkyl; or a 2-norbornylmethyl.

In one or more embodiments of the invention, a compound is provided, thecompound comprising a cannabinoid residue covalently attached via astable or degradable linkage to a water-soluble, non-peptidic oligomer,wherein the cannabinoid has a structure encompassed by the followingformula:

5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamideand enantiomers and diastereomers thereof.

In one or more embodiments of the invention, a compound is provided, thecompound comprising a cannabinoid residue covalently attached via astable or degradable linkage to a water-soluble, non-peptidic oligomer,wherein the cannabinoid has a structure encompassed by the followingformula:

1-(2,3-Dichlorobenzoyl)-5-methoxy-2-methyl-(3-(morpholin-4-yl)ethyl)-1H-indole,and enantiomers and diastereomers thereof.

In one or more embodiments of the invention, a compound is provided, thecompound comprising a cannabinoid residue covalently attached via astable or degradable linkage to a water-soluble, non-peptidic oligomer,wherein the cannabinoid has a structure encompassed by the followingformula:

(−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol,or Δ⁹-tetrahydrocannabinol (THC), or dronabinol, and enantiomers anddiastereomers thereof.

In one or more embodiments of the invention, a compound is provided, thecompound comprising a cannabinoid residue covalently attached via astable or degradable linkage to a water-soluble, non-peptidic oligomer,wherein the cannabinoid has a structure encompassed by the followingformula:

wherein R is

wherein R¹ is C₁-C₇ alkyl, R² is H or methyl, each R³ is individuallyhydrogen or C₁-C₄ alkanoyl, and wherein both R⁴ are the same and can behydrogen or methyl.

In one or more embodiments of the invention, a compound is provided, thecompound comprising a cannabinoid residue covalently attached via astable or degradable linkage to a water-soluble, non-peptidic oligomer,wherein the cannabinoid has a structure encompassed by the followingformula:

In some instances, cannabinoids can be obtained from commercial sources.In addition, cannabinoids can be obtained through chemical synthesis.Examples of cannabinoids as well as synthetic approaches for preparingcannabinoids are described in the literature and in, for example, U.S.Pat. No. 5,624,941 (Rimonabant), and Valenzano, K. J. et al.,Pharmacological and pharmcokinetic characterization of the cannabanoidreceptor 2 agonist, GW405833, utilizing rodent models of acute andchronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48,658-672, (2005) (BW405833), U.S. Pat. No. 3,968,125 (for nabilone). Eachof these (and other) cannabinoids can be covalently attached (eitherdirectly or through one or more atoms) to a water-soluble, non-peptidicoligomer.

Exemplary compounds of the invention include those having the followingstructure:

wherein:g₂, g₃, g₄, g₅, and g₆ and w₂, w₃, w₄, w₅ and w₆ are identical ordifferent and are independently hydrogen, a chlorine atom or a bromineatom, a (C₁-C₃)-alkyl, a (C₁-C₃)-alkoxy, a trifluoromethyl or a nitrogroup and g₄ is optionally a phenyl group;R₄ is hydrogen or a (C₁-C₃)-alkyl;A is either a direct bond or a group —(CH₂)_(x)—N(R₃)—, in which R₃ ishydrogen or a (C₁-C₃)-alkyl and x is zero or one; and,R₁ is a (C₁-C₆)-alkyl; an optionally-substituted non-aromatic (C₃-C₁₅)carbocyclic radical; an amino (C₁-C₄) alkyl group in which the amino isoptionally disubstituted by a (C₁-C₃)-alkyl; a cycloalkyl-(C₁-C₃) alkylin which the cycloalkyl is C₃-C₁₂; a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, by a (C₁-C₅)-alkyl orby a (C₁-C₅)-alkoxy; a phenyl (C₁-C₃)-alkyl; a diphenyl-(C₁-C₃)-alkyl; anaphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclicradical which is unsubstituted or substituted by a (C₁-C₃)-alkyl, by ahydroxyl or by a benzyl group; a 1-adamantylmethyl; an aromaticheterocycle unsubstituted, mono- or polysubstituted by a halogen, a(C₁-C₅)-alkyl, a (C₁-C₅)-alkoxy; a (C₁-C₃)-alkyl substituted by anaromatic heterocycle unsubstituted or mono- or polysubstituted by ahalogen, a (C₁-C₅) alkyl, or a (C₁-C₅)-alkoxy;X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

wherein:g₂, g₃, g₅, and g₆ and w₂, w₃, w₄, w₅ and w₆ are identical or differentand are independently hydrogen, a chlorine atom or a bromine atom, a(C₁-C₃)-alkyl, a (C₁-C₃)-alkoxy, a trifluoromethyl or a nitro group andg₄ is optionally a phenyl group;R₄ is hydrogen or a (C₁-C₃)-alkyl;A is either a direct bond or a group —(CH₂)_(x)—N(R₃)—, in which R₃ ishydrogen or a (C₁-C₃)-alkyl and x is zero or one; and,R₁ is a (C₁-C₆)-alkyl; an optionally-substituted non-aromatic (C₃-C₁₅)carbocyclic radical; an amino (C₁-C₄) alkyl group in which the amino isoptionally disubstituted by a (C₁-C₃)-alkyl; a cycloalkyl-(C₁-C₃) alkylin which the cycloalkyl is C₃-C₁₂; a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, by a (C₁-C₅)-alkyl orby a (C₁-C₅)-alkoxy; a phenyl (C₁-C₃)-alkyl; a diphenyl-(C₁-C₃)-alkyl; anaphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclicradical which is unsubstituted or substituted by a (C₁-C₃)-alkyl, by ahydroxyl or by a benzyl group; a 1-adamantylmethyl; an aromaticheterocycle unsubstituted, mono- or polysubstituted by a halogen, a(C₁-C₅)-alkyl, a (C₁-C₅)-alkoxy; a (C₁-C₃)-alkyl substituted by anaromatic heterocycle unsubstituted or mono- or polysubstituted by ahalogen, a (C₁-C₅) alkyl, or a (C₁-C₅)-alkoxy;X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

wherein:g₂, g₃, g₄, g₅, and g₆ and w₃, w₄, w₅ and w₆ are identical or differentand are independently hydrogen, a chlorine atom or a bromine atom, a(C₁-C₃)-alkyl, a (C₁-C₃)-alkoxy, a trifluoromethyl or a nitro group andg₄ is optionally a phenyl group;R₄ is hydrogen or a (C₁-C₃)-alkyl;A is either a direct bond or a group —(CH₂)_(x)—N(R₃)—, in which R₃ ishydrogen or a (C₁-C₃)-alkyl and x is zero or one; and,R₁ is a (C₁-C₆)-alkyl; an optionally-substituted non-aromatic (C₃-C₁₅)carbocyclic radical; an amino (C₁-C₄) alkyl group in which the amino isoptionally disubstituted by a (C₁-C₃)-alkyl; a cycloalkyl-(C₁-C₃) alkylin which the cycloalkyl is C₃-C₁₂; a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, by a (C₁-C₅)-alkyl orby a (C₁-C₅)-alkoxy; a phenyl (C₁-C₃)-alkyl; a diphenyl-(C₁-C₃)-alkyl; anaphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclicradical which is unsubstituted or substituted by a (C₁-C₃)-alkyl, by ahydroxyl or by a benzyl group; a 1-adamantylmethyl; an aromaticheterocycle unsubstituted, mono- or polysubstituted by a halogen, a(C₁-C₅)-alkyl, a (C₁-C₅)-alkoxy; a (C₁-C₃)-alkyl substituted by anaromatic heterocycle unsubstituted or mono- or polysubstituted by ahalogen, a (C₁-C₅) alkyl, or a (C₁-C₅)-alkoxy;X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

wherein:g₂, g₃, g₄, g₅, and g₆ and w₂, w₃, w₅ and w₆ are identical or differentand are independently hydrogen, a chlorine atom or a bromine atom, a(C₁-C₃)-alkyl, a (C₁-C₃)-alkoxy, a trifluoromethyl or a nitro group andg₄ is optionally a phenyl group;R₄ is hydrogen or a (C₁-C₃)-alkyl;A is either a direct bond or a group —(CH₂)_(x)—N(R₃)—, in which R₃ ishydrogen or a (C₁-C₃)-alkyl and x is zero or one; and,R₁ is a (C₁-C₆)-alkyl; an optionally-substituted non-aromatic (C₃-C₁₅)carbocyclic radical; an amino (C₁-C₄) alkyl group in which the amino isoptionally disubstituted by a (C₁-C₃)-alkyl; a cycloalkyl-(C₁-C₃) alkylin which the cycloalkyl is C₃-C₁₂; a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, by a (C₁-C₅)-alkyl orby a (C₁-C₅)-alkoxy; a phenyl (C₁-C₃)-alkyl; a diphenyl-(C₁-C₃)-alkyl; anaphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclicradical which is unsubstituted or substituted by a (C₁-C₃)-alkyl, by ahydroxyl or by a benzyl group; a 1-adamantylmethyl; an aromaticheterocycle unsubstituted, mono- or polysubstituted by a halogen, a(C₁-C₅)-alkyl, a (C₁-C₅)-alkoxy; a (C₁-C₃)-alkyl substituted by anaromatic heterocycle unsubstituted or mono- or polysubstituted by ahalogen, a (C₁-C₅) alkyl, or a (C₁-C₅)-alkoxy;X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention may utilize one or morepositions of the defined structures of formulae I an II to attach thelinker X to the water-soluble, non-peptidic oligomer.

Further exemplary compounds of the invention include those having thefollowing structure:

X is a spacer moiety; andPOLY is a water-soluble, non-peptidic oligomer.

Use of discrete oligomers (e.g., from a monodisperse or bimodalcomposition of oligomers, in contrast to relatively impure compositions)to form oligomer-containing compounds may advantageously alter certainproperties associated with the corresponding small molecule drug. Forinstance, a compound of the invention, when administered by any of anumber of suitable administration routes, such as parenteral, oral,transdermal, buccal, pulmonary, or nasal, exhibits reduced penetrationacross the blood-brain barrier. It is preferred that the compounds ofthe invention exhibit slowed, minimal or effectively no crossing of theblood-brain barrier, while still crossing the gastro-intestinal (GI)walls and into the systemic circulation if oral delivery is intended.Moreover, the compounds of the invention maintain a degree ofbioactivity as well as bioavailability in comparison to the bioactivityand bioavailability of the compound free of all oligomers.

With respect to the blood-brain barrier (“BBB”), this barrier restrictsthe transport of drugs from the blood to the brain. This barrierconsists of a continuous layer of unique endothelial cells joined bytight junctions. The cerebral capillaries, which comprise more than 95%of the total surface area of the BBB, represent the principal route forthe entry of most solutes and drugs into the central nervous system.

For compounds whose degree of blood-brain barrier crossing ability isnot readily known, such ability may be determined using a suitableanimal model such as an in situ rat brain perfusion (“RBP”) model asdescribed herein. Briefly, the RBP technique involves cannulation of thecarotid artery followed by perfusion with a compound solution undercontrolled conditions, followed by a wash out phase to remove compoundremaining in the vascular space. (Such analyses may be conducted, forexample, by contract research organizations such as Absorption Systems,Exton, Pa.). In one example of the RBP model, a cannula is placed in theleft carotid artery and the side branches are tied off. A physiologicbuffer containing the analyte (typically but not necessarily at a 5micromolar concentration level) is perfused at a flow rate of about 10mL/minute in a single pass perfusion experiment. After 30 seconds, theperfusion is stopped and the brain vascular contents are washed out withcompound-free buffer for an additional 30 seconds. The brain tissue isthen removed and analyzed for compound concentrations via liquidchromatograph with tandem mass spectrometry detection (LC/MS/MS).Alternatively, blood-brain barrier permeability can be estimated basedupon a calculation of the compound's molecular polar surface area(“PSA”), which is defined as the sum of surface contributions of polaratoms (usually oxygens, nitrogens and attached hydrogens) in a molecule.The PSA has been shown to correlate with compound transport propertiessuch as blood-brain barrier transport. Methods for determining acompound's PSA can be found, e.g., in, Ertl, P., et al., J. Med. Chem.2000, 43, 3714-3717; and Kelder, J., et al., Pharm. Res. 1999, 16,1514-1519.

With respect to the blood-brain barrier, the water-soluble, non-peptidicoligomer-small molecule drug conjugate exhibits a blood-brain barriercrossing rate that is reduced as compared to the crossing rate of thesmall molecule drug not attached to the water-soluble, non-peptidicoligomer. Exemplary reductions in blood-brain barrier crossing rates forthe compounds described herein include reductions of: at least about 5%;at least about 10%; at least about 25%; at least about 30%; at leastabout 40%; at least about 50%; at least about 60%; at least about 70%;at least about 80%; or at least about 90%, when compared to theblood-brain barrier crossing rate of the small molecule drug notattached to the water-soluble oligomer. A preferred reduction in theblood-brain barrier crossing rate for a conjugate of the invention is atleast about 20%.

Assays for determining whether a given compound (regardless of whetherthe compound includes a water-soluble, non-peptidic oligomer or not) canact as a cannabinoid are known and/or may be prepared by one of ordinaryskill in the art and are further described infra.

Each of these (and other) cannabinoid moieties can be covalentlyattached (either directly or through one or more atoms) to awater-soluble, non-peptidic oligomer.

Exemplary molecular weights of small molecule drugs include molecularweights of: less than about 950; less than about 900; less than about850; less than about 800; less than about 750; less than about 700; lessthan about 650; less than about 600; less than about 550; less thanabout 500; less than about 450; less than about 400; less than about350; and less than about 300 Daltons.

The small molecule drug used in the invention, if chiral, may be in aracemic mixture, or an optically active form, for example, a singleoptically active enantiomer, or any combination or ratio of enantiomers(i.e., scalemic mixture). In addition, the small molecule drug maypossess one or more geometric isomers. With respect to geometricisomers, a composition can comprise a single geometric isomer or amixture of two or more geometric isomers. A small molecule drug for usein the present invention can be in its customary active form, or maypossess some degree of modification. For example, a small molecule drugmay have a targeting agent, tag, or transporter attached thereto, priorto or after covalent attachment of an oligomer. Alternatively, the smallmolecule drug may possess a lipophilic moiety attached thereto, such asa phospholipid (e.g., distearoylphosphatidylethanolamine or “DSPE,”dipalmitoylphosphatidylethanolamine or “DPPE,” and so forth) or a smallfatty acid. In some instances, however, it is preferred that the smallmolecule drug moiety does not include attachment to a lipophilic moiety.

The cannabinoid moiety for coupling to a water-soluble, non-peptidicoligomer possesses a free hydroxyl, carboxyl, thio, amino group, or thelike (i.e., “handle”) suitable for covalent attachment to the oligomer.In addition, the cannabinoid moiety may be modified by introduction of areactive group, preferably by conversion of one of its existingfunctional groups to a functional group suitable for formation of astable covalent linkage between the oligomer and the drug.

Accordingly, each oligomer is composed of up to three different monomertypes selected from the group consisting of: alkylene oxide, such asethylene oxide or propylene oxide; olefinic alcohol, such as vinylalcohol, 1-propenol or 2-propenol; vinyl pyrrolidone; hydroxyalkylmethacrylamide or hydroxyalkyl methacrylate, where alkyl is preferablymethyl; α-hydroxy acid, such as lactic acid or glycolic acid;phosphazene, oxazoline, amino acids, carbohydrates such asmonosaccharides, alditol such as mannitol; and N-acryloylmorpholine.Preferred monomer types include alkylene oxide, olefinic alcohol,hydroxyalkyl methacrylamide or methacrylate, N-acryloylmorpholine, andα-hydroxy acid. Preferably, each oligomer is, independently, aco-oligomer of two monomer types selected from this group, or, morepreferably, is a homo-oligomer of one monomer type selected from thisgroup.

The two monomer types in a co-oligomer may be of the same monomer type,for example, two alkylene oxides, such as ethylene oxide and propyleneoxide. Preferably, the oligomer is a homo-oligomer of ethylene oxide.Usually, although not necessarily, the terminus (or termini) of theoligomer that is not covalently attached to a small molecule is cappedto render it unreactive. Alternatively, the terminus may include areactive group. When the terminus is a reactive group, the reactivegroup is either selected such that it is unreactive under the conditionsof formation of the final oligomer or during covalent attachment of theoligomer to a small molecule drug, or it is protected as necessary. Onecommon end-functional group is hydroxyl or —OH, particularly foroligoethylene oxides.

The water-soluble, non-peptidic oligomer (e.g., “POLY” in variousstructures provided herein) can have any of a number of differentgeometries. For example, the water-soluble, non-peptidic oligomer can belinear, branched, or forked. Most typically, the water-soluble,non-peptidic oligomer is linear or is branched, for example, having onebranch point. Although much of the discussion herein is focused uponpoly(ethylene oxide) as an illustrative oligomer, the discussion andstructures presented herein can be readily extended to encompass anywater-soluble, non-peptidic oligomers described above.

The molecular weight of the water-soluble, non-peptidic oligomer,excluding the linker portion, is generally relatively low. Exemplaryvalues of the molecular weight of the water-soluble polymer include:below about 1500; below about 1450; below about 1400; below about 1350;below about 1300; below about 1250; below about 1200; below about 1150;below about 1100; below about 1050; below about 1000; below about 950;below about 900; below about 850; below about 800; below about 750;below about 700; below about 650; below about 600; below about 550;below about 500; below about 450; below about 400; below about 350;below about 300; below about 250; below about 200; and below about 100Daltons.

Exemplary ranges of molecular weights of the water-soluble, non-peptidicoligomer (excluding the linker) include: from about 100 to about 1400Daltons; from about 100 to about 1200 Daltons; from about 100 to about800 Daltons; from about 100 to about 500 Daltons; from about 100 toabout 400 Daltons; from about 200 to about 500 Daltons; from about 200to about 400 Daltons; from about 75 to 1000 Daltons; and from about 75to about 750 Daltons.

Preferably, the number of monomers in the water-soluble, non-peptidicoligomer falls within one or more of the following ranges: between about1 and about 30 (inclusive); between about 1 and about 25; between about1 and about 20; between about 1 and about 15; between about 1 and about12; between about 1 and about 10. In certain instances, the number ofmonomers in series in the oligomer (and the corresponding conjugate) isone of 1, 2, 3, 4, 5, 6, 7, or 8. In additional embodiments, theoligomer (and the corresponding conjugate) contains 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, or 20 monomers. In yet further embodiments, theoligomer (and the corresponding conjugate) possesses 21, 22, 23, 24, 25,26, 27, 28, 29 or 30 monomers in series. Thus, for example, when thewater-soluble, non-peptidic polymer includes CH₃—(OCH₂CH₂)_(n)—, “n” isan integer that can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30, andcan fall within one or more of the following ranges: between about 1 andabout 25; between about 1 and about 20; between about 1 and about 15;between about 1 and about 12; between about 1 and about 10.

When the water-soluble, non-peptidic oligomer has 1, 2, 3, 4, 5, 6, 7,8, 9, or 10 monomers, these values correspond to a methoxy end-cappedoligo(ethylene oxide) having a molecular weights of about 75, 119, 163,207, 251, 295, 339, 383, 427, and 471 Daltons, respectively. When theoligomer has 11, 12, 13, 14, or 15 monomers, these values correspond tomethoxy end-capped oligo(ethylene oxide) having molecular weightscorresponding to about 515, 559, 603, 647, and 691 Daltons,respectively.

When the water-soluble, non-peptidic oligomer is attached to thecannabinoid (in contrast to the step-wise addition of one or moremonomers to effectively “grow” the oligomer onto the cannabinoid), it ispreferred that the composition containing an activated form of thewater-soluble, non-peptidic oligomer be monodisperse. In thoseinstances, however, where a bimodal composition is employed, thecomposition will possess a bimodal distribution centering around any twoof the above numbers of monomers. For instance, a bimodal oligomer mayhave any one of the following exemplary combinations of monomersubunits: 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, and so forth;2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, and so forth; 3-4, 3-5, 3-6,3-7, 3-8, 3-9, 3-10, and so forth; 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, and soforth; 5-6, 5-7, 5-8, 5-9, 5-10, and so forth; 6-7, 6-8, 6-9, 6-10, andso forth; 7-8, 7-9, 7-10, and so forth; and 8-9, 8-10, and so forth.

In some instances, the composition containing an activated form of thewater-soluble, non-peptidic oligomer will be trimodal or eventetramodal, possessing a range of monomers units as previouslydescribed. Oligomer compositions possessing a well-defined mixture ofoligomers (i.e., being bimodal, trimodal, tetramodal, and so forth) canbe prepared by mixing purified monodisperse oligomers to obtain adesired profile of oligomers (a mixture of two oligomers differing onlyin the number of monomers is bimodal; a mixture of three oligomersdiffering only in the number of monomers is trimodal; a mixture of fouroligomers differing only in the number of monomers is tetramodal), oralternatively, can be obtained from column chromatography of apolydisperse oligomer by recovering the “center cut”, to obtain amixture of oligomers in a desired and defined molecular weight range.

It is preferred that the water-soluble, non-peptidic oligomer isobtained from a composition that is preferably unimolecular ormonodisperse. That is, the oligomers in the composition possess the samediscrete molecular weight value rather than a distribution of molecularweights. Some monodisperse oligomers can be purchased from commercialsources such as those available from Sigma-Aldrich, or alternatively,can be prepared directly from commercially available starting materialssuch as Sigma-Aldrich. Water-soluble, non-peptidic oligomers can beprepared as described in Chen Y., Baker, G. L., J. Org. Chem., 6870-6873(1999), WO 02/098949, and U.S. Patent Application Publication2005/0136031.

When present, the spacer moiety (through which the water-soluble,non-peptidic polymer is attached to the cannabinoid moiety) may be asingle bond, a single atom, such as an oxygen atom or a sulfur atom, twoatoms, or a number of atoms. A spacer moiety is typically but is notnecessarily linear in nature. The spacer moiety, “X,” is hydrolyticallystable, and is preferably also enzymatically stable. Preferably, thespacer moiety “X” is one having a chain length of less than about 12atoms, and preferably less than about 10 atoms, and even more preferablyless than about 8 atoms and even more preferably less than about 5atoms, whereby length is meant the number of atoms in a single chain,not counting substituents. For instance, a urea linkage such as this,R_(oligomer)NH—(C═O)—NH—R′_(drug), is considered to have a chain lengthof 3 atoms (—NH—C(O)—NH—). In selected embodiments, the linkage does notcomprise further spacer groups.

In some instances, the spacer moiety “X” comprises an ether, amide,urethane, amine, thioether, urea, or a carbon-carbon bond. Functionalgroups such as those discussed below, and illustrated in the examples,are typically used for forming the linkages. The spacer moiety may lesspreferably also comprise (or be adjacent to or flanked by) other atoms,as described further below.

More specifically, in selected embodiments, a spacer moiety of theinvention, X, may be any of the following: “—” (i.e., a covalent bond,that may be stable or degradable, between the cannabinoid residue andthe water-soluble, non-peptidic oligomer), —O—, —NH—, —S—, —C(O)—,—C(O)O—, —OC(O)—, —CH₂—C(O)O—, —CH₂—OC(O)—, —C(O)O—CH₂—, —OC(O)—CH₂—,C(O)—NH, NH—C(O)—NH, O—C(O)—NH, —C(S)—, —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—, —O—CH₂—, —CH₂—O—, —O—CH₂—CH₂—, —CH₂—O—CH₂—,—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—,—CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—, —CH₂—O—C₂—CH₂—CH₂—,—CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—CH₂—O—,—C(O)—NH—CH₂—, —C(O)—NH—CH₂—CH₂—, —CH₂—C(O)—NH—CH₂—, —CH₂—CH₂—C(O)—NH—,—C(O)—NH—CH₂—CH₂—CH₂—, —CH₂—C(O)—NH—CH₂—CH₂—, —CH₂—CH₂—C(O)—NH—CH₂—,—CH₂—CH₂—CH₂—C(O)—NH—, —C(O)—NH—CH₂—CH₂—CH₂—CH₂—,—CH₂—C(O)—NH—CH₂—CH₂—CH₂—, —CH₂—CH₂—C(O)—NH—CH₂—CH₂—,—CH₂—CH₂—CH₂—C(O)—NH—CH₂—, —CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—C(O)—NH—NH—C(O)—CH₂—, —CH₂—NH—C(O)—CH₂—,—CH₂—CH₂—NH—C(O)—CH₂—, —NH—C(O)—CH₂—CH₂—, —CH₂—NH—C(O)—CH₂—CH₂,—CH₂—CH₂—NH—C(O)—CH₂—CH₂, —C(O)—NH—CH₂—, —C(O)—NH—CH₂—CH₂—,—O—C(O)—NH—CH₂—, —O—C(O)—NH—CH₂—CH₂—, —NH—CH₂—, —NH—CH₂—CH₂—,—CH₂—NH—CH₂—, —CH₂—CH₂—NH—CH₂—, —C(O)—CH₂—, —C(O)—CH₂—CH₂—,—CH₂—C(O)—CH₂—, —CH₂—CH₂—C(O)—CH₂—, —CH₂—CH₂—C(O)—CH₂—CH₂—,—CH₂—CH₂—C(O)—, —CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—NH—,—CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—NH—C(O)—,—CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—NH—C(O)—CH₂—, bivalent cycloalkyl group,—N(R⁶)—, R⁶ is H or an organic radical selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl and substituted aryl. Additionalspacer moieties include, acylamino, acyl, aryloxy, alkylene bridgecontaining between 1 and 5 inclusive carbon atoms, alkylamino,dialkylamino having about 2 to 4 inclusive carbon atoms, piperidino,pyrrolidino, N-(lower alkyl)-2-piperidyl, morpholino, 1-piperizinyl,4-(lower alkyl)-1-piperizinyl, 4-(hydroxyl-lower alkyl)-1-piperizinyl,4-(methoxy-lower alkyl)-1-piperizinyl, and guanidine. In some instances,a portion or a functional group of the drug compound may be modified orremoved altogether to facilitate attachment of the oligomer. In someinstances, it is preferred that X is not an amide, i.e., —CONR— or—RNCO—).

For purposes of the present invention, however, a group of atoms is notconsidered a linkage when it is immediately adjacent to an oligomersegment, and the group of atoms is the same as a monomer of the oligomersuch that the group would represent a mere extension of the oligomerchain.

The linkage “X” between the water-soluble, non-peptidic oligomer and thesmall molecule is typically formed by reaction of a functional group ona terminus of the oligomer (or nascent oligomer when it is desired to“grow” the oligomer onto the cannabinoid) with a correspondingfunctional group within the cannabinoid. Illustrative reactions aredescribed briefly below. For example, an amino group on an oligomer maybe reacted with a carboxylic acid or an activated carboxylic acidderivative on the small molecule, or vice versa, to produce an amidelinkage. Alternatively, reaction of an amine on an oligomer with anactivated carbonate (e.g. succinimidyl or benzotriazolyl carbonate) onthe drug, or vice versa, forms a carbamate linkage. Reaction of an amineon an oligomer with an isocyanate (R—N═C═O) on a drug, or vice versa,forms a urea linkage (R—NH—(C═O)—NH—R′). Further, reaction of an alcohol(alkoxide) group on an oligomer with an alkyl halide, or halide groupwithin a drug, or vice versa, forms an ether linkage. In yet anothercoupling approach, a small molecule having an aldehyde function iscoupled to an oligomer amino group by reductive amination, resulting information of a secondary amine linkage between the oligomer and thesmall molecule.

A particularly preferred water-soluble, non-peptidic oligomer is anoligomer bearing an aldehyde functional group. In this regard, theoligomer will have the following structure:CH₃O—(CH₂—CH₂—O)_(n)—(CH₂)_(p)—C(O)H, wherein (n) is one of 1, 2, 3, 4,5, 6, 7, 8, 9 and 10 and (p) is one of 1, 2, 3, 4, 5, 6 and 7. Preferred(n) values include 3, 5 and 7 and preferred (p) values 2, 3 and 4.

The termini of the water-soluble, non-peptidic oligomer not bearing afunctional group are capped to render it unreactive. When the oligomerincludes a further functional group at a terminus other than thatintended for formation of a conjugate, that group is either selectedsuch that it is unreactive under the conditions of formation of thelinkage “X,” or it is protected during the formation of the linkage “X.”

As stated above, the water-soluble, non-peptidic oligomer includes atleast one functional group prior to conjugation. The functional grouptypically comprises an electrophilic or nucleophilic group for covalentattachment to a small molecule, depending upon the reactive groupcontained within or introduced into the small molecule. Examples ofnucleophilic groups that may be present in either the oligomer or thesmall molecule include hydroxyl, amine, hydrazine (—NHNH₂), hydrazide(—C(O)NHNH₂), and thiol. Preferred nucleophiles include amine,hydrazine, hydrazide, and thiol, particularly amine. Most small moleculedrugs for covalent attachment to an oligomer will possess a freehydroxyl, amino, thio, aldehyde, ketone, or carboxyl group.

Examples of electrophilic functional groups that may be present ineither the oligomer or the small molecule include carboxylic acid,carboxylic ester, particularly imide esters, orthoester, carbonate,isocyanate, isothiocyanate, aldehyde, ketone, thione, alkenyl, acrylate,methacrylate, acrylamide, sulfone, maleimide, disulfide, iodo, epoxy,sulfonate, thiosulfonate, silane, alkoxysilane, and halosilane. Morespecific examples of these groups include succinimidyl ester orcarbonate, imidazoyl ester or carbonate, benzotriazole ester orcarbonate, vinyl sulfone, chloroethylsulfone, vinylpyridine, pyridyldisulfide, iodoacetamide, glyoxal, dione, mesylate, tosylate, andtresylate (2,2,2-trifluoroethanesulfonate).

Also included are sulfur analogs of several of these groups, such asthione, thione hydrate, thioketal, 2-thiazolidine thione, etc., as wellas hydrates or protected derivatives of any of the above moieties (e.g.aldehyde hydrate, hemiacetal, acetal, ketone hydrate, hemiketal, ketal,thioketal, thioacetal).

An “activated derivative” of a carboxylic acid refers to a carboxylicacid derivative that reacts readily with nucleophiles, generally muchmore readily than the underivatized carboxylic acid. Activatedcarboxylic acids include, for example, acid halides (such as acidchlorides), anhydrides, carbonates, and esters. Such esters includeimide esters, of the general form —(CO)O—N[(CO)—]₂; for example,N-hydroxysuccinimidyl (NHS) esters or N-hydroxyphthalimidyl esters. Alsopreferred are imidazolyl esters and benzotriazole esters. Particularlypreferred are activated propionic acid or butanoic acid esters, asdescribed in co-owned U.S. Pat. No. 5,672,662. These include groups ofthe form —(CH₂)₂₋₃C(═O)O-Q, where Q is preferably selected fromN-succinimide, N-sulfosuccinimide, N-phthalimide, N-glutarimide,N-tetrahydrophthalimide, N-norbornene-2,3-dicarboximide, benzotriazole,7-azabenzotriazole, and imidazole.

Other preferred electrophilic groups include succinimidyl carbonate,maleimide, benzotriazole carbonate, glycidyl ether, imidazoyl carbonate,p-nitrophenyl carbonate, acrylate, tresylate, aldehyde, and orthopyridyldisulfide.

These electrophilic groups are subject to reaction with nucleophiles,e.g., hydroxy, thio, or amino groups, to produce various bond types.Preferred for the present invention are reactions which favor formationof a hydrolytically stable linkage. For example, carboxylic acids andactivated derivatives thereof, which include orthoesters, succinimidylesters, imidazolyl esters, and benzotriazole esters, react with theabove types of nucleophiles to form esters, thioesters, and amides,respectively, of which amides are the most hydrolytically stable.Carbonates, including succinimidyl, imidazolyl, and benzotriazolecarbonates, react with amino groups to form carbamates. Isocyanates(R—N═C═O) react with hydroxyl or amino groups to form, respectively,carbamate (RNH—C(O)—OR′) or urea (RNH—C(O)—NHR′) linkages. Aldehydes,ketones, glyoxals, diones and their hydrates or alcohol adducts (i.e.,aldehyde hydrate, hemiacetal, acetal, ketone hydrate, hemiketal, andketal) are preferably reacted with amines, followed by reduction of theresulting imine, if desired, to provide an amine linkage (reductiveamination).

Several of the electrophilic functional groups include electrophilicdouble bonds to which nucleophilic groups, such as thiols, can be added,to form, for example, thioether bonds. These groups include maleimides,vinyl sulfones, vinyl pyridine, acrylates, methacrylates, andacrylamides. Other groups comprise leaving groups that can be displacedby a nucleophile; these include chloroethyl sulfone, pyridyl disulfides(which include a cleavable S—S bond), iodoacetamide, mesylate, tosylate,thiosulfonate, and tresylate. Epoxides react by ring opening by anucleophile, to form, for example, an ether or amine bond. Reactionsinvolving complementary reactive groups such as those noted above on theoligomer and the small molecule are utilized to prepare the conjugatesof the invention.

In some instances the cannabinoid may not have a functional group suitedfor conjugation. In this instance, it is possible to modify (or“functionalize”) the “original” cannabinoid so that it does have afunctional group suited for conjugation. For example, if the cannabinoidhas an amide group, but an amine group is desired, it is possible tomodify the amide group to an amine group by way of a Hofmannrearrangement, Curtius rearrangement (once the amide is converted to anazide) or Lossen rearrangement (once amide is concerted to hydroxamidefollowed by treatment with tolyene-2-sulfonyl chloride/base).

It is possible to prepare a conjugate of small molecule cannabinoidbearing a carboxyl group wherein the carboxyl group-bearing smallmolecule cannabinoid is coupled to an amino-terminated oligomericethylene glycol, to provide a conjugate having an amide group covalentlylinking the small molecule cannabinoid to the oligomer. This can beperformed, for example, by combining the carboxyl group-bearing smallmolecule cannabinoid with the amino-terminated oligomeric ethyleneglycol in the presence of a coupling reagent, (such asdicyclohexylcarbodiimide or “DCC”) in an anhydrous organic solvent.

Further, it is possible to prepare a conjugate of a small moleculecannabinoid bearing a hydroxyl group wherein the hydroxyl group-bearingsmall molecule cannabinoid is coupled to an oligomeric ethylene glycolhalide to result in an ether (—O—) linked small molecule conjugate. Thiscan be performed, for example, by using sodium hydride to deprotonatethe hydroxyl group followed by reaction with a halide-terminatedoligomeric ethylene glycol.

Further, it is possible to prepare a conjugate of a small moleculecannabinoid moiety bearing a hydroxyl group wherein the hydroxylgroup-bearing small molecule cannabinoid moiety is coupled to anoligomeric ethylene glycol bearing an haloformate group [e.g.,CH₃(OCH₂CH₂)_(n)OC(O)-halo, where halo is chloro, bromo, iodo] to resultin a carbonate [—O—C(O)—O—] linked small molecule conjugate. This can beperformed, for example, by combining a cannabinoid moiety and anoligomeric ethylene glycol bearing a haloformate group in the presenceof a nucleophilic catalyst (such as 4-dimethylaminopyridine or “DMAP”)to thereby result in the corresponding carbonate-linked conjugate.

In another example, it is possible to prepare a conjugate of a smallmolecule cannabinoid bearing a ketone group by first reducing the ketonegroup to form the corresponding hydroxyl group. Thereafter, the smallmolecule cannabinoid now bearing a hydroxyl group can be coupled asdescribed herein.

In still another instance, it is possible to prepare a conjugate of asmall molecule cannabinoid bearing an amine group. In one approach, theamine group-bearing small molecule cannabinoid and an aldehyde-bearingoligomer are dissolved in a suitable buffer after which a suitablereducing agent (e.g., NaCNBH₃) is added. Following reduction, the resultis an amine linkage formed between the amine group of the aminegroup-containing small molecule cannabinoid and the carbonyl carbon ofthe aldehyde-bearing oligomer.

In another approach for preparing a conjugate of a small moleculecannabinoid bearing an amine group, a carboxylic acid-bearing oligomerand the amine group-bearing small molecule cannabinoid are combined,typically in the presence of a coupling reagent (e.g., DCC). The resultis an amide linkage formed between the amine group of the aminegroup-containing small molecule cannabinoid and the carbonyl of thecarboxylic acid-bearing oligomer.

While it is believed that the full scope of the conjugates disclosedherein behave as described, an optimally sized oligomer can beidentified as follows.

First, an oligomer obtained from a monodisperse or bimodal water solubleoligomer is conjugated to the small molecule drug. Preferably, the drugis orally bioavailable, and on its own, exhibits a non-negligibleblood-brain barrier crossing rate. Next, the ability of the conjugate tocross the blood-brain barrier is determined using an appropriate modeland compared to that of the unmodified parent drug. If the results arefavorable, that is to say, if, for example, the rate of crossing issignificantly reduced, then the bioactivity of conjugate is furtherevaluated. Preferably, the compounds according to the invention maintaina significant degree of bioactivity relative to the parent drug, i.e.,greater than about 30% of the bioactivity of the parent drug, or evenmore preferably, greater than about 50% of the bioactivity of the parentdrug.

The above steps are repeated one or more times using oligomers of thesame monomer type but having a different number of subunits and theresults compared.

For each conjugate whose ability to cross the blood-brain barrier isreduced in comparison to the non-conjugated small molecule drug, itsoral bioavailability is then assessed. Based upon these results, that isto say, based upon the comparison of conjugates of oligomers of varyingsize to a given small molecule at a given position or location withinthe small molecule, it is possible to determine the size of the oligomermost effective in providing a conjugate having an optimal balancebetween reduction in biological membrane crossing, oral bioavailability,and bioactivity. The small size of the oligomers makes such screeningsfeasible and allows one to effectively tailor the properties of theresulting conjugate. By making small, incremental changes in oligomersize and utilizing an experimental design approach, one can effectivelyidentify a conjugate having a favorable balance of reduction inbiological membrane crossing rate, bioactivity, and oralbioavailability. In some instances, attachment of an oligomer asdescribed herein is effective to actually increase oral bioavailabilityof the drug.

For example, one of ordinary skill in the art, using routineexperimentation, can determine a best suited molecular size and linkagefor improving oral bioavailability by first preparing a series ofoligomers with different weights and functional groups and thenobtaining the necessary clearance profiles by administering theconjugates to a patient and taking periodic blood and/or urine sampling.Once a series of clearance profiles have been obtained for each testedconjugate, a suitable conjugate can be identified.

Animal models (rodents and dogs) can also be used to study oral drugtransport. In addition, non-in vivo methods include rodent everted gutexcised tissue and Caco-2 cell monolayer tissue-culture models. Thesemodels are useful in predicting oral drug bioavailability.

To determine whether the cannabinoid or the conjugate of a cannabinoidand a water-soluble non-peptidic polymer has activity as a cannabinoidtherapeutic, it is possible to test such a compound. The cannabinoidcompounds may be tested using in vitro binding studies to receptorsusing various cell lines expressing these receptors that have becomeroutine in pharmaceutical industry. The compounds according to theinvention were subjected to biochemical tests.

The cannabinoid or the conjugate of a cannabinoid may exhibit a goodaffinity in vitro for the cannabinoid receptors in tests performed underthe experimental conditions, described by Devane et al., MolecularPharmacology, 1988, 34, 605-613.

The cannabinoid or the conjugate of a cannabinoid may also possess anaffinity for the cannabinoid receptors present on preparations ofelectrically stimulated, isolated organs. These tests may be performedon the guinea-pig ileum and on the mouse vas deferens according toRoselt et al., Acta Physiologica Scandinavia, 1975, 94, 142-144, andaccording to Nicolau et al., Arch. Int. Pharmacodyn., 1978, 236,131-136.

In addition, the cannabinoid or the conjugate of a cannabinoid mayimprove the memory capacities of rats in the test of the central memory(A Perio et al., in Psychopharmacology, 1989, 97, 262-268).

The present invention also includes pharmaceutical preparationscomprising a conjugate as provided herein in combination with apharmaceutical excipient. Generally, the conjugate itself will be in asolid form (e.g., a precipitate), which can be combined with a suitablepharmaceutical excipient that can be in either solid or liquid form.

Exemplary excipients include, without limitation, those selected fromthe group consisting of carbohydrates, inorganic salts, antimicrobialagents, antioxidants, surfactants, buffers, acids, bases, andcombinations thereof.

A carbohydrate such as a sugar, a derivatized sugar such as an alditol,aldonic acid, an esterified sugar, and/or a sugar polymer may be presentas an excipient. Specific carbohydrate excipients include, for example:monosaccharides, such as fructose, maltose, galactose, glucose,D-mannose, sorbose, and the like; disaccharides, such as lactose,sucrose, trehalose, cellobiose, and the like; polysaccharides, such asraffinose, melezitose, maltodextrins, dextrans, starches, and the like;and alditols, such as mannitol, maltitol, lactitol, xylitol, sorbitol,myoinositol, and the like.

The excipient can also include an inorganic salt or buffer such ascitric acid, sodium chloride, potassium chloride, sodium sulfate,potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic,and combinations thereof.

The preparation may also include an antimicrobial agent for preventingor deterring microbial growth. Nonlimiting examples of antimicrobialagents suitable for the present invention include benzalkonium chloride,benzethonium chloride, benzyl alcohol, cetylpyridinium chloride,chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate,thimersol, and combinations thereof.

An antioxidant can be present in the preparation as well. Antioxidantsare used to prevent oxidation, thereby preventing the deterioration ofthe conjugate or other components of the preparation. Suitableantioxidants for use in the present invention include, for example,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorous acid, monothioglycerol, propyl gallate, sodiumbisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, andcombinations thereof.

A surfactant may be present as an excipient. Exemplary surfactantsinclude: polysorbates, such as “Tween 20” and “Tween 80,” and pluronicssuch as F68 and F88 (both of which are available from BASF, Mount Olive,N.J.); sorbitan esters; lipids, such as phospholipids such as lecithinand other phosphatidylcholines, phosphatidylethanolamines, fatty acidsand fatty esters; steroids, such as cholesterol; and chelating agents,such as EDTA, zinc and other such suitable cations.

Pharmaceutically acceptable acids or bases may be present as anexcipient in the preparation. Nonlimiting examples of acids that can beused include those acids selected from the group consisting ofhydrochloric acid, acetic acid, phosphoric acid, citric acid, malicacid, lactic acid, formic acid, trichloroacetic acid, nitric acid,perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, andcombinations thereof. Examples of suitable bases include, withoutlimitation, bases selected from the group consisting of sodiumhydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide,ammonium acetate, potassium acetate, sodium phosphate, potassiumphosphate, sodium citrate, sodium formate, sodium sulfate, potassiumsulfate, potassium fumerate, and combinations thereof.

The amount of the conjugate in the composition will vary depending on anumber of factors, but will optimally be a therapeutically effectivedose when the composition is stored in a unit dose container. Atherapeutically effective dose can be determined experimentally byrepeated administration of increasing amounts of the conjugate in orderto determine which amount produces a clinically desired endpoint.

The amount of any individual excipient in the composition will varydepending on the activity of the excipient and particular needs of thecomposition. Typically, the optimal amount of any individual excipientis determined through routine experimentation, i.e., by preparingcompositions containing varying amounts of the excipient (ranging fromlow to high), examining the stability and other parameters, and thendetermining the range at which optimal performance is attained with nosignificant adverse effects.

Generally, however, excipients will be present in the composition in anamount of about 1% to about 99% by weight, preferably from about 5%-98%by weight, more preferably from about 15-95% by weight of the excipient,with concentrations less than 30% by weight most preferred.

These foregoing pharmaceutical excipients along with other excipientsand general teachings regarding pharmaceutical compositions aredescribed in “Remington: The Science & Practice of Pharmacy”, 19^(th)ed., Williams & Williams, (1995), the “Physician's Desk Reference”,52^(nd) ed., Medical Economics, Montvale, N.J. (1998), and Kibbe, A. H.,Handbook of Pharmaceutical Excipients, 3^(rd) Edition, AmericanPharmaceutical Association, Washington, D.C., 2000.

The pharmaceutical compositions can take any number of forms and theinvention is not limited in this regard. Exemplary preparations are mostpreferably in a form suitable for oral administration such as a tablet,caplet, capsule, gel cap, troche, dispersion, suspension, solution,elixir, syrup, lozenge, transdermal patch, spray, suppository, andpowder.

Oral dosage forms are preferred for those conjugates that are orallyactive, and include tablets, caplets, capsules, gel caps, suspensions,solutions, elixirs, and syrups, and can also comprise a plurality ofgranules, beads, powders or pellets that are optionally encapsulated.Such dosage forms are prepared using conventional methods known to thosein the field of pharmaceutical formulation and described in thepertinent texts.

Tablets and caplets, for example, can be manufactured using standardtablet processing procedures and equipment. Direct compression andgranulation techniques are preferred when preparing tablets or capletscontaining the conjugates described herein. In addition to theconjugate, the tablets and caplets will generally contain inactive,pharmaceutically acceptable carrier materials such as binders,lubricants, disintegrants, fillers, stabilizers, surfactants, coloringagents, flow agents, and the like. Binders are used to impart cohesivequalities to a tablet, and thus ensure that the tablet remains intact.Suitable binder materials include, but are not limited to, starch(including corn starch and pregelatinized starch), gelatin, sugars(including sucrose, glucose, dextrose and lactose), polyethylene glycol,waxes, and natural and synthetic gums, e.g., acacia sodium alginate,polyvinylpyrrolidone, cellulosic polymers (including hydroxypropylcellulose, hydroxypropyl methylcellulose, methyl cellulose,microcrystalline cellulose, ethyl cellulose, hydroxyethylcellulose, andthe like), and Veegum. Lubricants are used to facilitate tabletmanufacture, promoting powder flow and preventing particle capping(i.e., particle breakage) when pressure is relieved. Useful lubricantsare magnesium stearate, calcium stearate, and stearic acid.Disintegrants are used to facilitate disintegration of the tablet, andare generally starches, clays, celluloses, algins, gums, or crosslinkedpolymers. Fillers include, for example, materials such as silicondioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose,and microcrystalline cellulose, as well as soluble materials such asmannitol, urea, sucrose, lactose, dextrose, sodium chloride, andsorbitol. Stabilizers, as well known in the art, are used to inhibit orretard drug decomposition reactions that include, by way of example,oxidative reactions.

Capsules are also preferred oral dosage forms, in which case theconjugate-containing composition can be encapsulated in the form of aliquid or gel (e.g., in the case of a gel cap) or solid (includingparticulates such as granules, beads, powders or pellets). Suitablecapsules include hard and soft capsules, and are generally made ofgelatin, starch, or a cellulosic material. Two-piece hard gelatincapsules are preferably sealed, such as with gelatin bands or the like.

Included are parenteral formulations in the substantially dry form(typically as a lyophilizate or precipitate, which can be in the form ofa powder or cake), as well as formulations prepared for injection, whichare typically liquid and requires the step of reconstituting the dryform of parenteral formulation. Examples of suitable diluents forreconstituting solid compositions prior to injection includebacteriostatic water for injection, dextrose 5% in water,phosphate-buffered saline, Ringer's solution, saline, sterile water,deionized water, and combinations thereof.

In some cases, compositions intended for parenteral administration cantake the form of nonaqueous solutions, suspensions, or emulsions, eachtypically being sterile. Examples of nonaqueous solvents or vehicles arepropylene glycol, polyethylene glycol, vegetable oils, such as olive oiland corn oil, gelatin, and injectable organic esters such as ethyloleate.

The parenteral formulations described herein can also contain adjuvantssuch as preserving, wetting, emulsifying, and dispersing agents. Theformulations are rendered sterile by incorporation of a sterilizingagent, filtration through a bacteria-retaining filter, irradiation, orheat.

The conjugate can also be administered through the skin usingconventional transdermal patch or other transdermal delivery system,wherein the conjugate is contained within a laminated structure thatserves as a drug delivery device to be affixed to the skin. In such astructure, the conjugate is contained in a layer, or “reservoir,”underlying an upper backing layer. The laminated structure can contain asingle reservoir, or it can contain multiple reservoirs.

The conjugate can also be formulated into a suppository for rectaladministration. With respect to suppositories, the conjugate is mixedwith a suppository base material which is (e.g., an excipient thatremains solid at room temperature but softens, melts or dissolves atbody temperature) such as coca butter (theobroma oil), polyethyleneglycols, glycerinated gelatin, fatty acids, and combinations thereof.Suppositories can be prepared by, for example, performing the followingsteps (not necessarily in the order presented): melting the suppositorybase material to form a melt; incorporating the conjugate (either beforeor after melting of the suppository base material); pouring the meltinto a mold; cooling the melt (e.g., placing the melt-containing mold ina room temperature environment) to thereby form suppositories; andremoving the suppositories from the mold.

The invention also provides a method for administering a conjugate asprovided herein to a patient suffering from a condition that isresponsive to treatment with the conjugate. The method comprisesadministering, generally orally, a therapeutically effective amount ofthe conjugate (preferably provided as part of a pharmaceuticalpreparation). Other modes of administration are also contemplated, suchas pulmonary, nasal, buccal, rectal, sublingual, transdermal, andparenteral. As used herein, the term “parenteral” includes subcutaneous,intravenous, intra-arterial, intraperitoneal, intracardiac, intrathecal,and intramuscular injection, as well as infusion injections.

In instances where parenteral administration is utilized, it may benecessary to employ somewhat bigger oligomers than those describedpreviously, with molecular weights ranging from about 500 to 30K Daltons(e.g., having molecular weights of about 500, 1000, 2000, 2500, 3000,5000, 7500, 10000, 15000, 20000, 25000, 30000 or even more).

The method of administering may be used to treat any condition that canbe remedied or prevented by administration of the particular conjugate.Those of ordinary skill in the art appreciate which conditions aspecific conjugate can effectively treat. The actual dose to beadministered will vary depend upon the age, weight, and generalcondition of the subject as well as the severity of the condition beingtreated, the judgment of the health care professional, and conjugatebeing administered. Therapeutically effective amounts are known to thoseskilled in the art and/or are described in the pertinent reference textsand literature. Generally, a therapeutically effective amount will rangefrom about 0.001 mg to 1000 mg, preferably in doses from 0.01 mg/day to750 mg/day, and more preferably in doses from 0.10 mg/day to 500 mg/day.

The unit dosage of any given conjugate (again, preferably provided aspart of a pharmaceutical preparation) can be administered in a varietyof dosing schedules depending on the judgment of the clinician, needs ofthe patient, and so forth. The specific dosing schedule will be known bythose of ordinary skill in the art or can be determined experimentallyusing routine methods. Exemplary dosing schedules include, withoutlimitation, administration five times a day, four times a day, threetimes a day, twice daily, once daily, three times weekly, twice weekly,once weekly, twice monthly, once monthly, and any combination thereof.Once the clinical endpoint has been achieved, dosing of the compositionis halted.

All articles, books, patents, patent publications and other publicationsreferenced herein are incorporated by reference in their entireties. Inthe event of an inconsistency between the teachings of thisspecification and the art incorporated by reference, the meaning of theteachings in this specification shall prevail.

EXPERIMENTAL

It is to be understood that while the invention has been described inconjunction with certain preferred and specific embodiments, theforegoing description as well as the examples that follow are intendedto illustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

All non-PEG chemical reagents referred to in the appended examples arecommercially available unless otherwise indicated. The preparation ofPEG-mers is described in, for example, U.S. Patent ApplicationPublication No. 2005/0136031.

All ¹H NMR (nuclear magnetic resonance) data was generated by an NMRspectrometer manufactured by. A list of certain compounds as well as thesource of the compounds is provided below.

Example 1 Structure of GW405833-Oligomer Conjugate

n is from about 3 to about 25 oligomer units.

Structure of Rimonabant-Oligomer Conjugate:

n is from about 3 to about 25 oligomer units.

Structure of Dronabinol-Oligomer Conjugate:

n is from about 3 to about 25 oligomer units.

Example 2 Synthesis of Dronabilnol and Nabilone Analogues

Compounds 1 and 2 are prepared by derivatization of the correspondingphenols 3 and 4, as shown in below. Phenols 3 and 4 differ from theregulated drugs dronabinol and nabilone in that they have a hydroxylgroup at the 3-position rather than an alkyl group.

The elaboration of phenols 3 and 4 to the targeted compounds 1 and 2would proceed as outlined in Scheme 1 below. The mPEG alcohols 5 are allcommercially available. An example of the conversion of 5 to 6 (n=3) isfound in Org. Lett. (2004) 6(4), 469-472. An example of the alkylationof a phenol with 6 (n=3) can be found in J. Org. Chem. (2006), 71(20),7499-7508. The selective protection of the 1-hydroxyl groups of 3 and 4is carried out, followed by deprotection subsequent to the alkylation.Alternatively, the mPEG side chains are introduced earlier in theconstruction of the cores in a non-convergent approach.

The synthesis of racemic 13, wherein the 3-hydroxyl group of 4 isalkylated, is reported in J. Heterocyclic Chem. (1990) 27, 535-547. Anoverview of this synthesis is shown in Scheme 2 below. Utilization of aproper protecting group (R) in the transformation of 9 to 10 allows fora differentiation between the two hydroxyls. Compounds 13 and 14 areseparated by chromatography, and it should be noted that the relativestereochemistry is indicated and that each compound is racemic followingthis synthesis scheme.

The synthesis of (R,R)-4 is described in J. Org. Chem. (2006) 71,7800-7804 and shown below.

The following chemistry is analogous to that in Scheme 3 above and alsoreported in J. Med. Chem. (2005) 48(23), 7389-7399. Also, compound(R,R)-3 (19) is obtained as illustrated in Scheme 4. Instead of5-alkyl-1,3-resorcinol; 5-alkoxy-1,3-resorcinol is used. The double bondis then isomerized to give 20, the 3-OH protected analog of 3.

Chemistry reported in J. Amer. Chem. Soc. (1974) 96(16), 5860-5865 isused to condense 5-alkoxy-1,3-resorcinol with p-mentha-2,8-dien-1-olunder highly controlled conditions to afford the double bond in thecorrect position.

Example 3 Synthesis of Dronabinol and Nabilone Analogues

Rxn Scale Conditions Yield Comment 1 to 10.2 g K₂CO₃ (0.6 equiv), 10.06g The product was confirmed by 2 PhSH (0.55 equiv), (54%) ¹H NMR.Unreacted trans- PhMe, DMF, 120° C., limonene oxide (3.2 g, 33%) 20 hwas isolated as well. 2 to 10.0 g Oxone, MeOH, H₂O, 3a: 5.45 g Twodiastereomers were 3 0° C. to 23° C., 2 h (51%); isolated, andcharacterized by ¹H 3b: 2.83 NMR and MS analyses. (27%)

Synthesis of Diene-Ol

Rxn Scale Conditions Yield Comment 3a to 4.66 Piperidine, DMSO, 1.90 gProduct confirmed 4 g 170° C., 4 h (75%) by ¹H NMR analysis. 3b to 0.25Piperidine, DMSO, — No product observed 4 g 170° C., 4 h

Alkylation of Diene-Ol

Rxn Scale Conditions Yield Comment 5 to 9 0.15 g p-TsOH•H₂O, THF, 0° C.to rt 0.09 g Product confirmed by (34%) ¹H NMR 5 to 9 1.90 g p-TsOH•H₂O,THF, −50° C. 2.06 g Product confirmed by for 3 h, then rt, 1 h (62%) ¹HNMR

Cyclization

Rxn Scale Conditions Yield Comment 6 to 7 0.50 g BF₃•OEt₂ (3 equiv), —Crude ¹H NMR spectrum showed CH₂Cl₂, −78° C., 3 h, mostly SM;purification by column then −20° C., 1 h chromatography provided thefirst fraction (40 mg) with 1:1 mixture of product and SM (6 + 7). 6 to7 0.50 g BF₃•OEt₂ (1 equiv), — Mixture of 6 and 7 was observed inCH₂Cl₂, −10° C. to 0° the crude ¹H NMR spectrum. C., 2 h 6 to 7 0.50 gBF₃•OEt₂ (5 mol — Mixture of 6 and 7 was observed in %), CH₂Cl₂, 0° C.,the crude spectra; first fraction from 20 h column chromatography ismostly product. Traces of 8 observed in ¹H NMR spectrum. HPLC showed amixture of three compounds (6, 7, 8). 6 to 7 0.25 g SnCl₄ (1 equiv), 7 +8: Mixture of 7 and 8 by ¹H NMR MeNO₂, rt, 12 h 0.16 g analysis, 8 looksmajor. (64%)

Synthesis of Nabilone Analogues

Rxn Scale Conditions Yield Comment 2 + 3 + 4 to 0.95 g 5 (0.8 equiv),p-TsOH•H₂O 6 + 7 Inseparable mixture of 6 (1.0 equiv), THF, 0° C. to rt,(1.02 g) 6 and 7. 3 h 1 to 1.00 g Pd(OAc)₄ (1.2 equiv), 0.74 g 2/3/4 ≈5:2:3. 2 + 3 + 4 benzene, reflux, 2 h (71%) Characterized by ¹H NMR. 2 +3 + 4 to 0.73 g 5 (3.0 equiv), p-TsOH•H₂O 6: 0.42 Little byproduct 7 6(1.0 equiv), THF, 0° C., 1 h g (41%) observed. Most of 5 8: 0.35 removedfrom product g (29%) 6 after purifying twice. 8 to 6 0.34 g K₂CO₃ (3.0equiv), MeOH, 0.18 g Characterized by MS rt, 1 h (61%) and ¹H NMR.

Rxn Scale Conditions Yield Comment 6 + 7 to 9 + 10 0.31 g SnCl₄ (5.0equiv), 9 + 10 Separation of 9 and 10 is difficult by CH₃NO₂, rt, 20 h(0.22 g) column. Analytical samples obtained by prep TLC. 6 to 9 0.40 gSnCl₄ (10 equiv). 0.31 g Characterized by MS and ¹H NMR. CH₃NO₂, rt, 4 h(77%)

Rxn Scale Conditions Yield 9 to 12 0.30 g 11 (1.0 equiv), K₂CO₃ (3.0equiv), DMF, rt —

Rxn Scale Conditions Yield Comment 7 to 9 0.31 g 8 (1.0 equiv), K₂CO₃ —No reaction. (3.0 equiv), DMF, rt, 18 h 7 to 9 0.31 g 8 (1.0 equiv),K₂CO₃ — Mixture of 7, 9, 10, and 11 by (3.0 equiv), DMF, 50° C. LC-MSanalysis. 16 h, then 80 ° C., 3 h 7/9(10)/10(9)/11 ≈ 6:3:1:1 by LC-MS. 7to 9 0.31 g 8 (1.4 equiv), K₂CO₃ — Mixture of 7, 9, 10, and 11 by (3.0equiv), DMF, 80° C., LC-MS and ¹H NMR analyses. 16 h 7/9(10)/10(9)/11 ≈7:5:3:8 by ¹H NMR.

Other Approaches

Example 4 PATHUNTER β-Arrestin Assay Principle

The assay detects binding of an agonist to a CB1 or CB2 GPCR of interestby directly measuring β-arrestin binding to the GPCR. Once bound,complementation occurs between the two β-galactosidase components: theProLink tag is fused to the C-terminus of the GPCR of interest: theEnzyme Acceptor (EA) is attached to β-arrestin. These componentsinteract only when in close proximity, forming active β-gal enzyme thatconverts substrate to detectable signal. In Scintillation ProximityAssay decay energy of unbound radioligand is absorbed by the medium.Decay energy of a bound radioligand excites the bead scintillantresulting in light emission.

For functional activity testing, whole-cell assays are developed usingcommercial Fluorescent Imaging Plate Reader (“FLIPR”)-based calcium fluxassay kits or cAMP activation assays.

Example 5

The conjugates of the invention are tested for binding to cannabinoidreceptors present on preparations of electrically stimulated, isolatedorgans. These tests may be performed on the guinea-pig ileum and on themouse vas deferens. It is believe that these conjugates will havecannabinoid receptor binding activity and act as antagonist or agonistof cannabinoid receptors.

Example 6

Patients and subjects suffering from movement disorders and otherchronic pain conditions such as Parkinson's syndrome, chronic pain,dystonia and spasticity neurological disorders, fibromyalgia, multiplesclerosis, and the nausea of cancer chemotherapy are treated withconjugates of the invention, suitably prepared as a pharmaceuticalcomposition, that have shown effective binding to cannabinoid receptors.It is believed that such treatment will show improvement in thecondition treated as compared to no treatment or treatment with placebo.

What is claimed is:
 1. A compound having the following structure:

wherein X is a spacer moiety and POLY is a water-soluble, non-peptidicoligomer.
 2. The compound of claim 1, wherein the water-soluble,non-peptidic oligomer is a poly(alkylene oxide).
 3. The compound ofclaim 2, wherein the poly(alkylene oxide) is a poly(ethylene oxide). 4.The compound of claim 1, wherein water-soluble, non-peptidic oligomer ismade of between 1 and 30 monomers.
 5. The compound of claim 4, whereinthe water-soluble, non-peptidic oligomer is made of between 1 and 10monomers.
 6. The compound of claim 2, wherein the poly(alkylene oxide)includes an alkoxy or hydroxy end-capping moiety.
 7. The compound ofclaim 1, wherein X is selected from the group consisting of —O—, —S—,—NH—, —C(O)—NH—, —NH—C(O)—, —NH—C(O)—O—, —NH—C(O)—NH—, and a covalentbond.
 8. The compound of claim 1, wherein X is —O—.
 9. A compositioncomprising a compound of claim 1, and optionally, a pharmaceuticallyacceptable excipient.
 10. A composition of matter comprising a compoundof claim 1, wherein the compound is present in a dosage form.
 11. Acompound having the structure:

wherein n is an integer having a value of from 1 to
 9. 12. A compositioncomprising a compound of claim 11, and optionally, a pharmaceuticallyacceptable excipient.
 13. A composition of matter comprising a compoundof claim 11, wherein the compound is present in a dosage form.